Di(2-ethylhexyl)phthalate Induces Hepatocellular Adenoma in Transgenic Mice Carrying a Human Prototype c-Ha-ras Gene in a 26-Week Carcinogenicity Study

Abstract

To evaluate the transgenic mouse carrying a human prototype c-Ha-ras gene (rasH2 mouse) as a model for 26-week carcinogenicity tests, Di(2-ethylhexyl)phthalate (DEHP), a peroxisome proliferator, was administered to 15 rasH2 mice/sex/group at concentrations of 1,500, 3,000 or 6,000 ppm, and to 15 wild-type (non-Tg) mice/sex/group at a concentration of 6,000 ppm in their diets for 26 weeks. Survival rates and food consumption in the groups treated with DEHP and in the control group were similar. Body weight gain in rasH2 and non-Tg mice at 6,000 ppm in the terminal week decreased about 10% as compared to the control group. Common findings related to treatment with DEHP in rasH2 and non-Tg mice included hypertrophy with coarse granules and deposit of pigment in the liver, hydronephrosis and tubular regeneration in the kidney, focal atrophy in the testis, and increased eosinophilic body in the nasal cavity. Hepatocellular adenoma was induced by treatment with DEHP, and was confined to male rasH2; mice the incidence being 7%(1/15), 13%(2/15), and 27%(4/15) in the 1,500-, 3,000-, and 6,000-ppm group, respectively. Point mutation was not detected in codon 12 and 61 of human c-Ha-ras transgene upon DNA analyses on frozen samples taken from these hepatocellular adenomas. From the results obtained in this 26-week carcinogenicity study, it is concluded that DEHP is a hepato-carcinogen for transgenic mouse carrying a human prototype c-Ha-ras gene.

Twenty-six week carcinogenicity study of ampicillin in CB6F1-TgrasH2 mice.

“…Spleen Pigmentation* 1(7) 1 (7) 3(20) 2(13) 3(20) 1 (7) 1 (7) 1 (7) 3 (20) These tumors have been reported as MNU-induced tumors in Tg-rasH2 mice (Yamamoto et al, 1996 and, and their incidence in the present study is similar to that in the published reports (Torii et al, 2001;Toyosawa et al, 2001). In addition, a carcinoma in the mammary gland and a leiomyoma in the uterus were detected in the MNU group.…”

Hepatocarcinogenic Susceptibility of Fenofibrate and Its Possible Mechanism of Carcinogenicity in a Two-Stage Hepatocarcinogenesis Model of rasH2 Mice

“…Based on this information, the new guidelines provided by the FDA for compounds in this class indicate that the carcinogenic potential of these PPAR agonists cannot be evaluated in TG or KO mice, and clinical studies longer than six months in duration cannot be initiated until two-year rodent carcinogenicity studies are completed and submitted for the agency to review (El-Hage 2004). On the other hand, it is well recognized that rasH2 mice, hemizygous transgenic mice carrying the human prototype c-Ha-ras gene with its own promoter and enhancer, are susceptible not only to genotoxic carcinogens but also to some non-genotoxic carcinogens classified as PPARα agonists, such as clofibrate, diethyl hexylphalate (DEHP), and Wy-14643 (Nesfield et al 2005;Toyosawa et al 2001;Yamamoto et al 1996). This means that in the absence of a database on rasH2 mice, the FDA recognizes the insusceptibility of these TG and KO mice to PPAR agonists.…”

Ftalan bis(2-etyloheksylu). Dokumentacja proponowanych dopuszczalnych wielkości narażenia zawodowego

“…Wyniki badań wykazały istotne zwiększenie częstości występowania jedynie gruczolaków wątroby wśród samców myszy rasH2 po narażeniu na największe stężenie ftalanu bis(2-etyloheksylu) w paszy (6 000 ppm). Pozostałe przypadki nowotworów (w tym płuc) nie były istotne statystycznie (Toyosawa i in. 2001; Usui i in.…”